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Exp. Biol. Med:柔红霉素可使心脏中E3泛素连接酶上调

  1. 柔红霉素
  2. 心脏
  3. 泛素连接酶

来源:生物谷 2012-02-22 20:41

近日,南非和挪威的研究人员发现柔红霉素治疗与心脏中的E3泛素连接酶上调有关。相关论文发表在Experimental Biology and Medicine上。 柔红霉素(daunorubicin,DNR)和阿霉素(doxorubicin,DOX)是两种主要的治疗全身肿瘤和固体瘤的有效蒽环类药物,然而较大的毒性限制了它们在临床上的应用。柔红霉素损伤心脏的机制仍有待查明。

近日,南非和挪威的研究人员发现柔红霉素治疗与心脏中的E3泛素连接酶上调有关。相关论文发表在Experimental Biology and Medicine上。

柔红霉素(daunorubicin,DNR)和阿霉素(doxorubicin,DOX)是两种主要的治疗全身肿瘤和固体瘤的有效蒽环类药物,然而较大的毒性限制了它们在临床上的应用。柔红霉素损伤心脏的机制仍有待查明。

近期的研究表明,阿霉素可以刺激泛素蛋白酶体降解某些特定的转录因子。而柔红霉素对于E3连接酶、MURF-1(muscle ring finger)和MAFbx(muscle atrophy F-box)的作用却没有任何报道。

此项研究的目的是调查柔红霉素对于心脏中的蛋白质和细胞器降解系统的影响,并阐明所涉及的一些信号机制。

研究人员将成年大鼠随机分成两组,一组隔日腹腔内注射2mg/Kg柔红霉素,共注射6次;另一组作为对照组,注射生理盐水。

生化分析表明,柔红霉素能够显著的衰减心脏功能,促进心脏细胞的凋亡,其诱发的心脏毒性与E3连接酶、MURF-1和MAFbx的上调有关,也可导致细胞自噬的两种标志分子beclin-1和LC3显著上升。柔红霉素还可衰减PI3-kinase/Akt信号途径。(生物谷Bioon.com)

Daunorubicin therapy is associated with upregulation of E3 ubiquitin ligases in the heart

Balindiwe J N Sishi, Dirk J Bester, Anita Wergeland, Benjamin Loos, Anne K Jonassen, Jacques van Rooyen and Anna-Mart Engelbrecht

Daunorubicin (DNR) and doxorubicin (DOX) are two of the most effective anthracycline drugs known for the treatment of systemic neoplasms and solid tumors. However, their clinical use is hampered due to profound cardiotoxicity. The mechanism by which DNR injures the heart remains to be fully elucidated. Recent reports have indicated that DOX activates ubiquitin proteasome-mediated degradation of specific transcription factors; however, no reports exist on the effect of DNR on the E3 ubiquitin ligases, MURF-1 (muscle ring finger 1) and MAFbx (muscle atrophy F-box). The aim of this study was to investigate the effect of DNR treatment on the protein and organelle degradation systems in the heart and to elucidate some of the signalling mechanisms involved. Adult rats were divided into two groups where one group received six intraperitoneal injections of 2 mg/kg DNR on alternate days and the other group received saline injections as control. Hearts were excised and perfused on a working heart system the day after the last injection and freeze-clamped for biochemical analysis. DNR treatment significantly attenuated cardiac function and increased apoptosis in the heart. DNR-induced cardiac cytotoxicity was associated with upregulation of the E3 ligases, MURF-1 and MAFbx and also caused significant increases in two markers of autophagy, beclin-1 and LC3. These changes observed in the heart were also associated with attenuation of the phosphoinositide 3-kinase/Akt signalling pathway.

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